Structural basis for conformational plasticity of the Parkinson's disease-associated ubiquitin hydrolase UCH-L1 Academic Article uri icon

Overview

MeSH Major

  • Parkinson Disease
  • Ubiquitin Thiolesterase

abstract

  • The ubiquitin C-terminal hydrolase UCH-L1 (PGP9.5) comprises >1% of total brain protein but is almost absent from other tissues [Wilkinson, K. D., et al. (1989) Science 246, 670-673]. Mutations in the UCH-L1 gene have been reported to be linked to susceptibility to and protection from Parkinson's disease [Leroy, E., et al. (1998) Nature 395, 451-452; Maraganore, D. M., et al. (1999) Neurology 53, 1858-1860]. Abnormal overexpression of UCH-L1 has been shown to correlate with several forms of cancer [Hibi, K., et al. (1998) Cancer Res. 58, 5690-5694]. Because the amino acid sequence of UCH-L1 is similar to that of other ubiquitin C-terminal hydrolases, including the ubiquitously expressed UCH-L3, which appear to be unconnected to neurodegenerative disease, the structure of UCH-L1 and the effects of disease associated mutations on the structure and function are of considerable importance. We have determined the three-dimensional structure of human UCH-L1 at 2.4-A resolution by x-ray crystallography. The overall fold resembles that of other ubiquitin hydrolases, including UCH-L3, but there are a number of significant differences. In particular, the geometry of the catalytic residues in the active site of UCH-L1 is distorted in such a way that the hydrolytic activity would appear to be impossible without substrate induced conformational rearrangements.

publication date

  • March 21, 2006

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC1450230

Digital Object Identifier (DOI)

  • 10.1073/pnas.0510403103

PubMed ID

  • 16537382

Additional Document Info

start page

  • 4675

end page

  • 80

volume

  • 103

number

  • 12